Both human and laboratory animal research findings strongly implicate brain noradrenergic overactivity and norepinephrine (NE) depletion in the neuropathology of major depressive disorder (MDD). Over past years, this laboratory has generated evidence of neurochemical pathology of the major source of brain NE, the locus coeruleus (LC) in MDD and in suicide, consistent with the overactivity/depletion hypothesis. Recent findings of deficits in glia in MDD have raised interest in the communication between noradrenergic neurons and glia in depression. Glia express receptors for NE and respond to NE activation of these receptors. In some brain regions noradrenergic signaling in the brain occurs primarily through glia. In return, noradrenergic neurons receive information from glia via neurotrophic factors. Recent findings from this lab demonstrate altered glutamate signaling in the LC in MDD. One source of this abnormality may be glia, since glia express glutamate receptors and transporters and contribute substantially to glutamate uptake. NE regulates astrocytic glutamate uptake, and thus, reduced NE in MDD may contribute to deficient glutamate uptake by glia in the LC, increasing excitatory actions of glutamate in the LC. In addition, preliminary findings demonstrate reduced levels of bone morphogenetic protein-7 (BMP7), one of several neurotrophins produced by glia, in the LC of MDD relative to control subjects. BMP7 regulates the health of noradrenergic neurons, and interestingly, glutamate opposes its action. Given evidence of pathologies of both NE neurons and glia, the overall hypothesis of this application is that MDD is associated with altered bi-directional communication between noradrenergic neurons and glia. Disrupted glutamate signaling and reduced BMP7 in the LC of MDD subjects provide preliminary support for this hypothesis. The aims of this proposal focus investigation of noradrenergic neuron-glial communication in the LC, a nucleus that consists of NE neurons and glia. Postmortem brain tissues from psychiatrically characterized subjects, both control (no psychiatric diagnosis) and antidepressant-free subjects with MDD, will be studied. Laser capture microdissection and polymerase chain reaction methods will be employed to study LC neurons, astrocytes, and oligodendrocytes, 3 major cell types in the LC. The expression of several relevant glutamate-related, neurotrophic factor-related, and noradrenergic signaling genes will be measured in the LC from assiduously matched control and MDD subjects. Immunohistochemistry and Western blotting will be used to verify changes in protein levels of those mRNAs that demonstrate difference between control and MDD subjects. Finally, the density of neuronal dendrites and glia in the LC will be studied in control and MDD subjects. This research will test the plausible hypothesis that dysfunction of noradrenergic neurons is closely associated with glial disruption in MDD, and holds the promise of identifying pathological markers that may ultimately reveal novel and possibly improved therapeutic targets for the treatment of this debilitating disorder. Project PUBLIC HEALTH RELEVANCE Major depressive disorder is a biological and behavioral disorder, with treatments that are often either ineffective or incompletely effective. This research aims to elucidate the neuropathology of major depression by studying a key region of the brain where antidepressant drugs are known to produce robust effects on activity and function, using postmortem brain tissue from major depressive subjects and accidental/natural death control subjects. Understanding the molecular pathology of this disorder holds the promise of identifying new biological targets for the development of improved treatments.